Treatment of growth failure associated with chronic kidney disease up until the time of renal transplantation (Nutropin, Nutropin AQ).

Treatment of growth failure in children born small for gestational age who fail to manifest catch-up growth by 2 years of age (Genotropin, Omnitrope) or by 2 to 4 years of age (Humatrope, Norditropin, Zomacton)

Treatment of idiopathic short stature (nongrowth hormone-deficient short stature), defined by height standard deviation score (SDS) ≤-2.25 and growth rate not likely to attain adult height in the normal range, in pediatric patients whose epiphyses are not closed and for whom other causes associated with short stature have been excluded (Genotropin, Humatrope, Norditropin, Nutropin, Nutropin AQ, Omnitrope, Zomacton).

Adult-onset: Patients who have adult growth hormone deficiency whether alone or with multiple hormone deficiencies (hypopituitarism) as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma

or

Childhood-onset: Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes, confirmed as an adult before replacement therapy is initiated

Patients with Prader-Willi syndrome who have a history of upper airway obstruction or sleep apnea (Genotropin, Humatrope, Norditropin, Nutropin, Nutropin AQ, Omnitrope, Zomacton)

Dosing: Adult

Note: Nutropin (lyophilized powder) has been discontinued in the US for more than 1 year.

Growth hormone deficiency: Adjust dose based on individual requirements: To minimize adverse events in older or overweight patients, reduced dosages may be necessary. During therapy, dosage should be decreased if required by the occurrence of side effects or excessive IGF-I levels.

Weight-based dosing:Note: Obese patients are more likely to experience adverse effects when treated with a weight-based regimen; use is not recommended.

Norditropin: SubQ: Initial dose: 0.004 mg/kg/day; dose may be increased up to a maximum of 0.016 mg/kg/day.

Nutropin, Nutropin AQ: SubQ: ≤0.006 mg/kg/day; dose may be increased up to a maximum of 0.025 mg/kg/day in patients ≤35 years, or up to a maximum of 0.0125 mg/kg/day in patients >35 years

Humatrope: SubQ: ≤0.006 mg/kg/day; dose may be increased up to a maximum of 0.0125 mg/kg/day

Genotropin, Omnitrope: SubQ: Weekly dosage: ≤0.04 mg/kg divided into equal doses 6 to 7 days per week; dose may be increased at 4- to 8-week intervals to a maximum of 0.08 mg/kg/week

HIV-associated adipose redistribution syndrome (HARS) (off-label use): Serostim: SubQ: Induction: 4 mg once daily at bedtime for 12 weeks; Maintenance: 2 mg or 4 mg every other day at bedtime for 12 to 24 weeks. Note: Every-other-day dosing during induction has also been studied. Although a greater response was seen with daily dosing, it was associated with an increased incidence of adverse events (Grunfeld 2007; Kotler 2004).

HIV-associated wasting, cachexia:

Serostim: SubQ: Initial: 0.1 mg/kg once daily at bedtime (maximum: 6 mg/day); patients at risk for side effects (eg, glucose intolerance) may be started at 0.1 mg/kg every other day. Adjust dose (ie, reduce the total daily dose or the number of doses per week) if needed to manage side effects.

Severe toxicity: Discontinue therapy for up to 5 days; when symptoms resolve, restart at 50% of dose. If severe toxicity recurs or does not disappear within 5 days after discontinuation, permanently discontinue treatment.

Saizen: SubQ: Weekly dosage: 0.18 mg/kg divided into equal daily doses or as 0.06 mg/kg/dose administered 3 days per week or as 0.03 mg/kg/dose administered 6 days per week.

Tev-Tropin: SubQ: ≤0.1 mg/kg/dose 3 days per week.

Zomacton: SubQ: Weekly dosage: 0.18 to 0.3 mg/kg/week (0.026 to 0.043 mg/kg/day) divided into equal doses and administered either 3, 6, or 7 days per week.

Note: Therapy should be discontinued when patient has reached satisfactory height, when epiphyses have fused, or when the patient ceases to respond. Some guidelines recommend discontinuing therapy when growth velocity is <2 to 2.5 cm/year (Grimberg 2016).

Alternate dosing (small for gestational age): In older/pubertal children or children with very short stature (ie, height SDS <-3), consider initiating therapy at higher doses (eg, 0.067 mg/kg/day [0.48 mg/kg/week]) and then consider gradually reducing the dose if substantial catch-up growth observed during the first few years of therapy. In younger children (~<4 years) with less severe short stature (ie, baseline height SDS values between -2 and -3), consider initiating therapy with lower doses (eg, 0.033 mg/kg/day) and then titrating the dose upwards as needed.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; decreased clearance in patients with chronic renal failure and end-stage renal disease.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; reduced clearance in patients with severe hepatic impairment.

Reconstitution

Genotropin:

Cartridge: Reconstitute with diluent provided.

MiniQuick: Reconstitute with diluent provided. Consult the instructions provided with the reconstitution device.

Humatrope:

Cartridge: Consult HumatroPen User Guide for complete instructions for reconstitution. Dilute with solution provided with cartridges ONLY; do not use diluent provided with vials.

Vial: Reconstitute with 1.5 to 5 mL diluent provided. Swirl gently; do not shake. If sensitivity to the diluent occurs, reconstitute with bacteriostatic water for injection (benzyl alcohol preserved) or sterile water for injection. Reconstitute with sterile water for injection for use in newborns.

Nutropin: Reconstitute each vial with 1 to 10 mL bacteriostatic water for injection (benzyl alcohol preserved). Swirl gently, do not shake. If sensitivity to the diluent occurs or for use in newborns, reconstitute with sterile water for injection.

Nutropin AQ: Allow device to come to room temperature and gently swirl; if solution is cloudy, do not use.

Vial: Reconstitute 5 mg vial with 1 to 3 mL and 8.8 mg vial with 2 to 3 mL bacteriostatic water for injection (benzyl alcohol preserved). If sensitivity to the diluent occurs, reconstitute with sterile water for injection. Gently swirl; do not shake.

Serostim:

4 mg vial: Reconstitute with 0.5 to 1 mL bacteriostatic water for injection (benzyl alcohol preserved). For patients sensitive to benzyl alcohol, reconstitute with sterile water for injection.

5 or 6 mg vial: Reconstitute with 0.5 to 1 mL sterile water for injection.

Tev-Tropin: Note: Only use the provided diluent for the 5 mg and 10 mg vial; diluents differ, do not interchange. Some cloudiness may occur; do not use if cloudiness persists after warming to room temperature.

5 mg vial: Reconstitute with 1 to 5 mL of provided diluent. Swirl gently; do not shake. If sensitivity to the diluent occurs or for use in newborns, reconstitute with sterile water for injection.

Zomacton: Note: Only use the provided diluent for the 5 mg and 10 mg vial; diluents differ, do not interchange. Some cloudiness may occur; do not use if cloudiness persists after warming to room temperature.

5 mg vial: Reconstitute with 1 to 5 mL of provided diluent. Swirl gently; do not shake. If sensitivity to the diluent occurs or for use in newborns, pregnancy or breastfeeding, reconstitute with normal saline.

Zorbtive: Reconstitute with 1 to 2 mL of diluent based on patient weight. Swirl gently; do not shake. The provided diluent is bacteriostatic water for injection preserved with benzyl alcohol; sterile water for injection may be used in patients unable to receive benzyl alcohol. If powder is reconstituted with provided diluent and stored prior to use, allow refrigerated solution to come to room temperature prior to administration.

Administration

Storage

Genotropin:

Cartridge: Store at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Following reconstitution, may store under refrigeration for up to 28 days.

Miniquick: Store at 2°C to 8°C (36°F to 46°F) prior to dispensing; may be stored ≤25°C (77°F) for up to 3 months after dispensing. Store in original carton to protect from light; do not freeze. Once reconstituted, solution must be refrigerated and used within 24 hours. Discard unused portion.

Humatrope:

Cartridge: Before and after reconstitution, store at 2°C to 8°C (36°F to 46°F); do not freeze. Following reconstitution with provided diluent, stable for 28 days under refrigeration.

Vial: Before and after reconstitution, store at 2°C to 8°C (36°F to 46°F); do not freeze. When reconstituted with provided diluent or bacteriostatic water for injection (benzyl alcohol preserved), use within 14 days. When reconstituted with sterile water for injection, use within 24 hours and discard unused portion.

Norditropin: Store at 2°C to 8°C (36°F to 46°F); do not freeze. Avoid direct light. Pens in use may be stored in refrigerator and used within 4 weeks after initial injection or may be stored up to 3 weeks at ≤25°C (77°F). Discard unused portion.

Nutropin: Before and after reconstitution, store at 2°C to 8°C (36°F to 46°F); do not freeze. Use vials reconstituted with bacteriostatic water for injection (benzyl alcohol preserved) within 14 days; when reconstituted with sterile water for injection, use immediately and discard unused portion.

Nutropin AQ: Before and after reconstitution, store at 2°C to 8°C (36°F to 46°F); do not freeze. Use within 28 days following initial use. Protect from light.

Omnitrope:

Cartridge: Store at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Once the cartridge is loaded into the pen delivery system, store under refrigeration for up to 28 days after first use.

Vial: Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Following reconstitution, store under refrigeration for up to 3 weeks. Store vial in carton to protect from light.

Saizen:

Cartridge: Store at 15°C to 30°C (59°F to 86°F). Following reconstitution with the provided diluent, store under refrigeration for up to 21 days. Avoid freezing.

Vial: Store at 15°C to 30°C (59°F to 86°F). Following reconstitution with bacteriostatic water for injection (benzyl alcohol preserved), store under refrigeration for up to 14 days. Following reconstitution with sterile water for injection, use immediately and discard unused portion. Avoid freezing.

Serostim: Prior to reconstitution, store at 15°C to 30°C (59°F to 86°F). Following reconstitution with sterile water for injection, use immediately and discard unused portion. Following reconstitution with bacteriostatic water for injection (benzyl alcohol preserved), store under refrigeration for up to 14 days; avoid freezing.

Tev-Tropin: Prior to reconstitution, store at 2°C to 8°C (36°F to 46°F). Following reconstitution with the provided diluent, store under refrigeration and use within 14 days (5 mg vial) or 28 days (10 mg vial); do not freeze.

Zomacton: Prior to reconstitution, store at 2°C to 8°C (36°F to 46°F). Following reconstitution with the provided diluent, store under refrigeration and use within 14 days (5 mg vial) or 28 days (10 mg vial); do not freeze. If the 5 mg vial is reconstituted with NS (instead of provided diluent), use immediately after reconstitution (for only one dose), then discard unused portion.

Zorbtive: Store intact vials and diluent at 15°C to 30°C (59°F to 86°F). Following reconstitution with the provided diluent (bacteriostatic water for injection containing benzyl alcohol), may store under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 14 days; do not freeze. If reconstituted with sterile water for injection, solution should be used immediately.

Local: Bleeding at injection site (children), burning sensation at injection site (children), erythema at injection site (children), fibrosis at injection site (children), inflammation at injection site (children), injection site nodule (children), injection site numbness (children), local skin hyperpigmentation (children; injection site), swelling at injection site (children)

• Intracranial hypertension: Intracranial hypertension with headache, nausea, papilledema, visual changes, and/or vomiting has been reported; symptoms usually occur within the first 8 weeks of therapy and signs and symptoms of intracranial hypertension may rapidly resolve after discontinuation or reduction of dose. Funduscopic examination prior to initiation of therapy and periodically thereafter is recommended. Treatment should be discontinued in patients who develop papilledema; resuming treatment at a lower dose may be considered once IH-associated signs and symptoms have resolved. Patients with Turner syndrome, chronic renal impairment and Prader-Willi syndrome may be at increased risk for intracranial hypertension.

• Lipoatrophy: Lipoatrophy has been reported at injection sites when used at the same site for a prolonged period. Ensure proper injection technique and rotate injection sites.

• Neoplasm: Increased risk of malignancy progression in patients with active malignancy; any preexisting malignancy should be inactive and treatment complete prior to initiating therapy; discontinue therapy with evidence of recurrence or progression. Monitor patients with preexisting tumors or growth hormone deficiency secondary to an intracranial lesion for recurrence or progression of underlying disease. An increased risk of second neoplasm has been reported in childhood cancer survivors treated with somatropin; the most common second neoplasms were meningiomas in patients treated with radiation to the head for their first neoplasm. Patients with HIV and pediatric patients with short stature (genetic cause) have increased baseline risk of developing malignancies; consider risk/benefits prior to initiation of therapy and monitor these patients carefully. Monitor all patients for any malignant transformation of skin lesions. Rule out pituitary tumor (or other brain tumors) prior to initiation of treatment because growth hormone deficiency may be an early sign of the presence of these tumors.

• Pancreatitis: Has been rarely reported; incidence in children (especially girls) with Turner syndrome may be greater than adults. Consider pancreatitis diagnosis if abdominal pain occurs.

• Slipped capital femoral epiphyses: Patients with endocrine disorders (including growth hormone deficiency and Turner syndrome) or in patients undergoing rapid growth may develop slipped capital femoral epiphyses more frequently; evaluate any child with new onset of a limp or with complaints of hip or knee pain.

Disease-related concerns:

• Acute critical illness: Initiation of somatropin is contraindicated with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure; mortality may be increased. Discontinuation of therapy may be necessary in patients with an acute critical illness.

• Childhood-onset adult growth hormone deficiency: Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin for growth hormone deficiency in adults.

• Chronic kidney disease: Periodically monitor children with growth failure secondary to chronic kidney disease (CKD) for evidence of progression of renal osteodystrophy. Slipped capital femoral epiphysis or avascular necrosis of the femoral head may be seen in children with advanced renal osteodystrophy. Obtain x-rays of the hip prior to initiating somatropin in CKD patients; be alert to the development of a limp or complaints of hip or knee pain.

• Hypoadrenalism: Patients who have or are at risk for pituitary hormone deficiency(ies) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism with somatropin therapy; patients with previously diagnosed hypoadrenalism may require increased dosages of glucocorticoids due to the effects of somatropin. Excessive glucocorticoid therapy may inhibit the growth-promoting effects of somatropin in children; monitor and adjust glucocorticoids carefully.

• Hypothyroidism: Patients who have or are at risk for pituitary hormone deficiency(ies) may be at risk for reduced thyroid function (central hypothyroidism) and patients with Turner syndrome have an increased risk of developing autoimmune thyroid disease and primary hypothyroidism. Untreated/undiagnosed hypothyroidism may decrease response to therapy, particularly the growth response in children. Monitor thyroid function periodically and initiate/adjust thyroid replacement therapy as needed.

• Noonan syndrome: Safety has not been established for the treatment of Noonan syndrome in children with significant cardiac disease.

• Prader-Willi syndrome: Fatalities have been reported in pediatric patients with Prader-Willi syndrome following the use of growth hormone. The reported fatalities occurred in patients with one or more risk factors, including severe obesity, history of upper airway obstruction or sleep apnea, respiratory impairment, or unidentified respiratory infection; male patients may be at greater risk. Monitor for sleep apnea, upper airway obstruction, and respiratory infections prior to initiation of therapy and periodically thereafter. Treatment interruption is recommended in patients who show signs of upper airway obstruction, including the onset of, or increased, snoring and/or new-onset sleep apnea. All patients with Prader-Willi syndrome should have effective weight control. Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, use is not indicated for the long-term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

• Scoliosis: Progression of scoliosis may occur in children experiencing rapid growth; monitor for worsening of scoliosis.

• Elderly: Elderly patients may be more sensitive to the actions of somatropin; consider lower starting doses and smaller dose increments.

• HIV patients: Patients with HIV infection should be maintained on antiretroviral therapy to prevent the potential increase in viral replication.

• Pediatric: Failure to increase growth rate, particularly during the first year of therapy, indicates need for close assessment of compliance and evaluation for other causes of growth failure, such as hypothyroidism, undernutrition, advanced bone age, and antibodies to recombinant human GH.

• Renal transplant recipients: No studies have been completed evaluating Nutropin or Nutropin AQ in patients with renal transplant. Use is not indicated in patients with functioning renal allografts.

• Multiple-dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC 2012).

Monitoring Parameters

Treatment of growth hormone deficiency (children): Growth response; funduscopic exam prior to treatment; progression of scoliosis in patients with a history of scoliosis; clinical evidence of slipped capital femoral epiphysis, such as a limp or hip or knee pain; thyroid function; glucose in patients with risk factors for glucose intolerance; progression or recurrence of tumor in patients treated for growth deficiency secondary to a tumor or tumor development in at risk patients; progression of pre-existing nevi. In addition, guidelines recommend a physical exam at every visit; monitoring serum IGF-I; adrenal and thyroid function in patients with growth hormone deficiency due to multiple pituitary hormone deficiencies; funduscopic exam if symptoms of intracranial hypertension occur (Grimberg [PES 2016])

Short bowel syndrome: Diet should be optimized prior to therapy and nutritional status monitored during treatment; colonoscopy prior to therapy (in patients with residual colon) especially if risk factors for colon cancer are present (Steiger 2006). In addition, monitor for progression of preexisting nevi; glucose in patients with risk factors for glucose intolerance; thyroid function prior to and 4 weeks after treatment initiation in patients with suspected or diagnosed hypopituitarism; funduscopic examination at initiation of therapy

Pregnancy Risk Factor

B/C (depending upon manufacturer)

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies, however, reproduction studies have not been conducted with all agents. During normal pregnancy, maternal production of endogenous growth hormone decreases as placental growth hormone production increases. Data with somatropin use during pregnancy is limited (Vila 2015; Yoshizawa 2017) and recommendations related to use in pregnant women cannot be made (AACE [Cook 2009]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.